Antiinflammatory and anti-hyperproliferative naphthyridin-4-ones

ABSTRACT

Tricyclic pyrrolo naphthyridinone compounds and tricyclic pyrrolo pyrido pyrazines are disclosed, which are useful as antiinflammatory and anti-hyperproliferative agents.

BACKGROUND OF THE INVENTION

The present invention relates to novel tricyclic compounds that possessantiinflammatory and anti-hyperproliferative activity. Other tricyclicantiinflamatory agents have been disclosed in U.S. Pat. No. 4,680,298and published PCT application 86/01269.

SUMMARY OF THE INVENTION

The invention relates to a compound having the structural formula I##STR1## or pharmaceutically acceptable salts or solvates thereofwherein: R¹ is selected from H, alkyl, aryl, alkenyl, benzyl,substituted alkyl, subsituted aryl or substituted benzyl;

R² is selected from H, alkyl, aryl, alkenyl, benzyl, substituted alkyl,substituted aryl, substituted benzyl, --O(CO)--R⁸, D--NR⁵ R⁶, --D--OR⁷or --D--( CO)--OR⁸ wherein D is alkanediyl or a covalent bond;

R³ and R⁴ are the same or different and each is independently selectedfrom H, alkyl, aryl or heteroaryl;

R⁵ and R⁶ are the same or different and each is independently selectedfrom H or alkyl, or together represent alkanediyl;

R⁷ is selected from H, alkyl or aryl;

R⁸ is selected from alkyl, aryl, benzyl or substituted benzyl; and

X is selected from CH or N.

A preferred subgenus of compounds is that wherein:

R¹ is selected from H, phenyl, benzyl, substituted phenyl or substitutedbenzyl;

R² is selected from H, phenyl, substituted phenyl, alkyl, allyl,--O(CO)--R⁸, D--NR⁵ R⁶, --D--(CO)--OR⁸ wherein D is alkanediyl or abond;

R³ and R⁴ are the same or different and each is independently selectedfrom H or alkyl;

R⁵ and R⁶ are the same or different and each is independently selectedfrom H or alkyl, or together represent alkanediyl of from 1 to 8 carbonatoms;

R⁸ is selected from alkyl or aryl; and

X is selected from CH or N.

A more preferred subgenus of compounds is that wherein:

R¹ is phenyl and R² is selected from H, phenyl, benzyl or carbethoxy;

R³ and R⁴ are H; and

X is CH.

A still more preferred subgenus of compounds is that wherein:

R¹ is phenyl;

R² is selected from H, phenyl or carbethoxy;

R³ and R⁴ are H; and

X is CH.

Preferred species are those having the names:

1,2,3,5-tetrahydro-1,5-diphenyl-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-one;

1,2,3,5-tetrahydro-5-phenyl-1-(phenylmethyl)-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-one;

2,3,4,5-tetrahydro-4-oxo-5-phenyl-1H-pyrrolo[3,2-c[[1,8]naphthyridine-1-carboxylicacid, ethyl ester; or

1,2,3,5-tetrahydro-5-phenyl-4H-pyrrolo[3,2-c][1,8]naphthyridin-4one.

The invention also includes a pharmaceutical composition which comprisesa compound having structural formula I in combination with apharmaceutically acceptable carrier and a method for treatinginflammation or hyperproliferative skin disease in a mammal thatcomprises administering an antiinflammatory or antihyperproliferativeeffective amount, respectively, of the above-defined compound to saidmammal.

DESCRIPTION OF THE INVENTION

The starting materials having structural formulas II and III are knownin the art. U.S. Pat. No. 4,492,702 and EP Pat. No. 092786, whichdescribe the preparation of compounds of formula II, are herebyincorporated by reference. Also, U.S. Pat. No. 4,680,298 which describesthe preparation of compounds of formula III, is hereby incorporated byreference.

The compounds of formula I can be prepared by the processes A-G below,wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, D and X are as defined above unlessotherwise indicated.

A. Compounds of formula I wherein R² is R^(2a) and R^(2a) is selectedfrom alkyl, aryl, alkenyl, benzyl, substituted alkyl, substituted aryl,substitutled benzyl, --D--NR⁵ R⁶ or --DOR⁷ (I.e., a compound of formulaIa below) can be produced by the following reaction: ##STR2##

For example, Compound II may be treated with the amine (R^(2a) NH₂) inthe presence of a catalytic amount of acid and enough of a suitablesolvent, for example lower-alkyl alcohol such as ethanol (EtOH), todissolve the reagents. Preferably, the stoichiometry of Compound II:amine in the reaction is in the range of 1:1 to 1:10 and more preferablyabout 1:2. The acid can be any suitable strong acid including HCl ortoluenesulfonic acid. Preferably the reaction is carried out under aninert atmosphere such as N₂ or Ar. The reaction may be performed at anyeffective temperature but is preferably heated to a temperature of atleast about 100° C., preferably 100°-200° C. for an appropriate period,usually at least about 0.5 hours, preferably 0.5-3 hours. Morepreferably, the heating is at about 165° C. for about 1 hour. Thereaction mixture may be triturated with aqueous base, preferably NaOH,and extracted with an organic solvent such as CH₂ Cl₂ or ether. Theorganic layer is dried then evaporated. The residue can be purified bychromatography on silica and characterized and verified by TLC, spectralanalysis, melting point and elemental analysis.

B. Compounds of formula I wherein R² is R^(2a) as described above may beproduced by the following reaction: ##STR3##

A compound of Type III, prepared as described in U.S. Pat. No.4,680,298, is mixed with an amine R^(2a) --NH₂ (preferably an excess,more preferably 1 to 25 equivs.), which usually acts as the solvent. Themixture is preferably heated, more preferably to a temperature ofbetween about 100° C. and 240° C., most preferably in the range of 150°to 210° C. Preferably, the reaction is also carried out in an inertatmosphere such as N₂. The reaction progress may be followed by TLCand/or HPLC until the starting material is consumed. When the reactionis sufficiently complete the product is cooled and extracted into anorganic solvent, such as CH₂ Cl₂ and is purified by flash chromatographyon silica gel and characterized by spectral analysis, melting point andelemental analysis.

C. In addition, compounds of formula I wherein R² is R^(2a) as definedabove may be prepared by the following reaction: ##STR4##

Compound IV may be obtained as described in U.S. Pat. No. 4,680,298 andthe conditions for this reaction are essentially the same as those usedin the process described above in Section B.

D. Compounds of formula I wherein R¹ and R² are the same and both areselected from the group described for R¹ above may be produced by thefollowing reaction: ##STR5##

Compound V, whose synthesis is described in U.S. Pat. No. 4,680,298, isreacted with the amine R¹ NH₂ using the conditions and stoichiometriesdescribed above in section A for the reaction of Compound II with R²NH₂. Stoichiometries of at least 1:2 (Compound V: R¹ NH₂) are preferred.Characterization and verification of the product is as above.

E. Compounds of formula I wherein R² is H and R¹ is R^(1a) whereinR^(1a) is H, alkyl, aryl, alkenyl, substituted alkyl, substituted arylor substituted alkenyl (Compound Id) can be produced by the followingreaction: ##STR6##

Compound Ic (wherein the benzyl group may also be substituted) may bemixed with a suitable strong acid, e.g. 30% HBr/acetic acid. Preferablythe ratio of compound Ic to acid is from 1:1 to 1:10 w/w (CompoundIc:HBr solution). A ratio of 1:5 Compound Ic:HBr solution is morepreferable. The reaction occurs at any effective temperature, preferablybetween 20°-120° C., preferably under an inert atmosphere (pressureabout 1 atm) for at least 15 minutes, preferably 15 minutes to 4 hours.However, the reaction may be followed by TLC until sufficientlycomplete. Reaction at 90° C. under an N₂ Ar atmosphere for about 1 houris typical. The reaction mixture may be poured into water andneutralized to a pH of 4.0-8.0 (pH 5.0 is preferred). The product can becollected by filtration and characterized and verified as describedabove.

In addition, the benzyl (or substituted benzyl group) in the compound offormula Ic may be removed under standard hydrogenolysis conditions,e.g., by use of a suitable catalyst such as Pd on carbon under H₂ gas ina suitable solvent such as methanol, preferably in the presence of anacid such as acetic acid, HCl, trifluoroacetic acid, etc. The H₂pressure is preferably in the range of from about 1 to about 4atmospheres.

F. Compounds of formula I wherein R² is --D--C(O)OR⁸ (Compound Ie) canbe produced by the following reaction: ##STR7## wherein L is a suitableleaving group such as chloro, bromo, tosyl, mesyl, etc.

Compound Id may be reacted in a suitable solvent such as Ch₂ Cl₂ withL--D--(CO)OR⁸. Preferaby, a molar ratio of 1:1 to 1:10 (Compound Id:L--D--(CO)OR⁸) is employed. Suitable bases include triethylamine,pyridine, N,N-dimethylaminopyridine or K₂ CO₃. Preferably, the reactionproceeds for at least 2 hours, preferably 2-48 hours. A ratio of 1:2(Compound Id: solvent), the base N,N-dimethylaminopyridine and areaction time of about 24 hours are typical. The product (compound Ie)can be collected by filtration, washed with dilute acid such as 0.5NHCl, followed by washing with H₂ O and drying. The product can becharacterized and verified as described above.

G. The compounds of formula Ig (i.e., compounds of formula I wherein R²is --O(CO)--R⁸) may be prepared from compound If (compounds of formula Iwherein R² is OH) by the following reaction: ##STR8##

Compound If may be reacted with an acylating agent such as R⁸ (CO)L,wherein L is a suitable leaving agent such as Cl. The reaction mayproceed under standard conditions for acylation reactions, in thepresence of a suitable base, such as triethylamine (NEt₃). Standardconditions for acylation reactions are well known to those skilled inthe art.

When utilized herein and in the appended claims, the following terms,unless specified otherwise, are defined as:

alkyl--straight and branched saturated carbon chains containing from 1to 10 carbon atoms;

aryl--a carbocyclic group containing at least one benzene ring.Preferably the aryl groups contain from 6 to 15 carbon atoms, morepreferably being phenyl or substituted phenyl, e.g., phenyl, naphthyl,indenyl, indanyl, 4-chlorophenyl, 4-fluorophenyl, etc.;

alkenyl--straight and branched carbon chains containing one or morecarbon-carbon double bonds, attached to the nitrogen atom by a methylene(--CH₂ --), e.g., an allyl group;

alkanediyl--divalent, saturated straight and branched carbon chains,preferably containing 1-8 carbon atoms;

heteroaryl--aryl groups having at least one O, S and/or N hetero atominterrupting the ring structure and having a sufficient number ofunsaturated carbon to carbon bonds, nitrogen to carbon bonds, etc., toprovide aromatic character, with the aromatic heterocyclic groupspreferably containing from 2 to 14 carbon atoms, e.g., pyridyl, furyl,thienyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, benzofuranyl, indolyl, pyrazolyl, oxazolyl, etc. Manytimes such heterocyclic groups can be bonded via various carbon atoms onthe heterocyclic ring and all such variations are contemplated, e.g. 2-or 3-furanyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-imidazolyl, etc.;

halogen--fluorine, chlorine, bromine and iodine;

alkoxy--an alkyl radical attached to a molecule by oxygen;

substituted alkyl--an alkyl wherein one or more hydrogens is replaced byOH;

substituted aryl, substituted benzyl, or substituted phenyl--an aryl,benzyl or phenyl wherein one or more aromatic hydrogen is replaced bythe same or different substituents independently chosen from hydroxy,alkyl having from 1 to 6 carbon atoms, halogen, nitro, alkoxy havingfrom 1 to 6 carbon atoms, trifluoromethyl, cyano, cycloalkyl having from3 to 7 carbon atoms, alkenyloxy having from 3 to 6 carbon atoms,alkynyloxy having from 3 to 6 carbon atoms, S(O)_(p) R^(a) [wherein p is0, 1 or 2 and R^(a) is alkyl having from 1 to 6 carbon atoms].

Certain compounds of this invention may exist in isomeric forms. Theinvention contemplates all such isomers both in pure form and inadmixture, including racemic mixtures.

Certain compounds of the invention of formula I can exist in unsolvatedas well as solvated forms, including hydrated forms, e.g., hemihydrate.In general, the solvated forms, with pharmaceutically acceptablesolvents such as water, ethanol and the like are equivalent to theunsolvated forms for purposes of the invention.

Certain compounds of the invention will be acidic in nature, e.g. thosecompounds which possess a carboxyl or phenolic hydroxyl group. Thesecompounds may form pharmaceutically acceptable salts. Examples of suchsalt are the sodium, potassium, calcium, aluminum, gold and silversalts. Also contemplated are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkylamines, hydroxyalkylamines,N-methylglucamine and the like.

The antiinflammatory activity of the compounds can be demonstrated bystandard test procedures, such as the reversed passive arthus reaction(RPAR) as described below or as described in Myers et al., Inflammation9 (1):91-98 (1985).

The antiinflammatory activity and antiproliferative activity of thecompounds can be demonstrated by using the lipoxygenase assay describedbelow.

REVERSED PASSIVE ARTHUS REACTION (RPAR) ANIMALS, MATERIALS AND METHODS

Male Lewis inbred albino rats weighting 180-220 grams obtained fromCharles River Breeding Laboratories are used in these experiments. Therats are housed 3 animals/cage and food and water are allowed adlibitum. The animals are numbered 1-3 in each cage and color marked foridentification purposes.

All reagents and drugs are prepared just prior to the study.Crystallized and lyophilized bovine serum albumin (BSA), obtained fromSigma Chemical Company, is solubilized without shaking in cold sterilepyrogen free saline (10 mg/ml). Lyophilized anti-bovine serum albumin(IgG Fraction), obtained from Cappel Laboratories, is suspended insterile distilled water and diluted with cold pyrogen free saline (PFS)just prior to use. The final concentration of anti-bovine serum albuminis 0.5 mg/ml of PFS. Both BSA and anti-BSA solutions are iced duringuse. Drugs are suspended or solubilized in an aqueous solution of methylcellulose (MC) with a homogenizer just prior to administration.

Groups of animals (6/group) are dosed with drug in MC by gavage one hourprior to sensitization with BSA. Controls are given MC alone anddrug-standard is usually included in each assay for verificationpurposes. Drugs are prepared so as to provide a dose for a 200 gramanimal which is equivalent to the mg/kg dose for the experiment. Thuseach rat receives an oral dose in a volume of approximately 2.0 cc. Onehour after dosing the animals are lightly anesthetized with ether andsensitized by injecting into the penile vein 0.2 ml of PFS containing1.0 mg of BSA. One hour later they are injected in the plantar region ofone hind paw with 0.1 ml of PFS containing 1.0 mg of BSA. One hour laterthey are injected in the plantar region of one hind paw with 0.1 ml ofPFS containing 0.1 mg of the anti-bovine serum albumin. Immediatelyafter the subplantar injection, the injected paw is dipped (up to thelateral maleolus) into the mercury well of a plethylsmograph. The volumeof mercury displaced is converted to weight and recorded. This value isconsidered to be the control paw volume for the animal. Paw volumes arealso recorded with a plethysmograph during the development of theinflammation at 2 and 4 hours post-challenge. Compound 1,2,3,5tetrahydro-5-phenyl-4H-pyrrolo[3,2c][1,8]naphthyridin-4-one provided anED₅₀ value of about 25 mg/kg, p.o. in this procedure.

Another procedure for testing for acute antiinflammatory activitymeasures the reverse passive Arthus reaction in the pleural cavity ofrats as described in Myers et al., Inflammation, Vol. 9, No. 1, 1985,pp. 91-98. Compounds 1,2,3,5tetrahydro-5-phenyl-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-one and2,3,4,5-tetrahydro-4-oxo-5-phenyl-1H-pyrrolo[3,2-c][1,8]naphthyridin-1-carboxylicacid, ethyl ester provided ED₅₀ values of less than 25 mg/kg and about25 mg/kg respectively, p.o. in this procedure.

The effect of the compounds of the invention on 5-lipoxygenase activityis determined using rat neutrophils. Male Witar-Lewis rats are injectedintravenously with 5 mg BSA in 0.2 ml pyrogen free saline followed by anintrapleural injection of 500 ug of the IgG fraction of rabbit anti-BSA(Cappel Labs., Lot 17782) in 0.2 ml pyrogen free saline. Injections aremade under light ether anesthesia. Four hours later, the pleural cavityexudate consisting of 85 to 95% neutrophils is removed. Neutrophils areisolated from the pleural exudates by centrifugation of 4° C. for 10 minat 200× g. The cell pellet is resuspended in 17 mM Tris is HCl buffer,pH 7.2, containing 0.75% NH₄ Cl to lyse contaminating erythrocytesfollowed by centrifugation at 4° C. for 5 min at 200× g. The pelletedneutrophils are rewashed in 50 mM Tris HCl, pH 7.4, containing 100 mMNaCl, followed by the same centrifugation. The cell pellet isresuspended in 50 mM Tris HCl, pH 7.4, containing 100 mM NaCl and 1 mMCaCl₂, at 3-12×10⁷ intact neutrophils per ml.

Solutions of compounds in methanol are dried, then resuspended in thecell suspension for 4 min. Arachidonic acid methabolism is determined byincubating 0.1 ml of this suspension with 40 μM [1-¹⁴ C] arachidonicacid (AA) (Amersham, 59 Ci/mole), in the presence of 0.1% BRIJ 56 and 10μM A23187. Arachidonic acid metabolism as well as the various drug andreagent abbreviations are described in detail in Arch. Dermatol, Vol.119, pages 541 to 547 (July 1983), the teachings of which areincorporated herein by reference. Assays run in triplicate are initiatedby adding cells with inhibitor to a film of the BRIJ 56, arachidonicacid and A23187 37° C. After one minute, reactions are terminated by theaddition of 2.4 ml of a chloroform:methanol (1:1 v/v) mixture and 0.9 mlof 0.1% formic acid. The suspension is vortexed, immediately cooled onice, centrifuged, and the organic layer withdrawn. The extract isevaporated under a stream of N₂ and resuspended in 0.1 mlchloroform:methanol (2:1 v/v) for spotting on thin layer plates (SilG-25, without gypsum, Brinkmann). Chromatograms are developed withether:methanol (80:20) for 2 cm, dried, and redeveloped with ligroine:diethylether:glacial acetic acid (40:60:1 v/v/v) for an additional 20cm. Products, leukotriene B₄ (LTB₄), 12-hydroxy heptadecatrienoic acid(HHT) and 5-hydroxy icosatetraenoic acid (5-HETE), are located byautoradiography and appropriate regions of the thin layer plates arescraped and counted in a liquid scintillation counter. Metabolites areidentified by co-chromatography with authentic standards.

Compound1,2,3,5-tetrahydro-1,5-diphenyl-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-oneshowed about 40% inhibition of HHT production and 60% inhibition of HETEand LTB₄ production when the compound was present in a concentration of5×10⁻⁵ Molar.

The compounds in this invention can thus be used to treat inflammationand hyperproliferative skin diseases.

As used herein, the term "hyperproliferative skin disease" means anycondition a symptom of which is accelerated skin cell production,flaking, scales or papular lesions, including, for example psoriasis,eczema, dandruff and the like.

In the preferred antiinflammation use, the compounds of this inventionare used to treat patients by administering an anti-inflammatoryeffective amount thereof.

The active compounds can be administered orally, topically,parenterally, or by oral or nasal inhalation. The preferred mode ofadministration is orally or intravenously.

Formulations for topical application, e.g., for use in treatinghyperproliferative skin diseases, may include the above liquid forms,creams, aerosols, sprays, dusts, powders, lotions and ointments whichare prepared by combining an active ingredient according to thisinvention with conventional pharmaceutical diluents and carrierscommonly used in topical dry, liquid, cream and aerosol formulations.Ointment and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Such bases may, thus, for example, include water and/or an oilsuch as liquid paraffin or a vegetable oil such as peanut oil or castoroil. Thickening agents which may be used according to the nature of thebase include soft paraffin, aluminum stearate, cetostearyl alcohol,propylene glycol, polyethylene glycols, woolfat, hydrogenated lanolin,beeswax, etc.

Lotions may be formulations with an aqueous or oily base and will, ingeneral, also include one or more of the following, namely, stabilizingagents, emulsifying agents, dispersing agents, suspending agents,thickening agents, coloring agents, perfumes and the like.

Powders may be formed with the aid of any suitable powder base, e.g.,talc, lactose, starch, etc. Drops may be formulated with an aqueous baseor non-aqueous base also comprising one or more dispersing agents,suspending agents, solubilizing agents, etc.

The topical pharmaceutical compositions according to the invention mayalso include one or more preservatives or bacteriostatic agents, e.g.,methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol,benzalkonium chlorides, etc.

The topical pharmaceutical compositions according to the invention mayalso contain other active ingredients such as antimicrobial agents,particularly antibiotics, anesthetics, analgesics and antipruriticagents.

The amount and frequency of administration will be regulated accordingto the judgement of the attending clinician considering such factors asage, condition and size of the patient as well as severity of thedisease being treated. A typical recommended dosage regimen for treatinginflammation is oral administration of from 0.5 to 50 mg/kg/daypreferably 2 to 40 mg/kg/day, in two to four divided doses to achieverelief of the symptoms. Alternatively, intravenous administration of 0.1to 10 mg/kg/day is recommended, preferably 0.6 to 8 mg/kg/day in two tofour divided doses to achieve relief of the inflammation symptoms. Whenadministered orally or parenterally for the treatment ofhyperproliferative skin disease, the compounds may be administered in anamount ranging from about 0.01 mg/kg to about 100 mg/kg, and preferablyfrom about 0.1 mg/kg to about 10 mg/kg. When administered topically, thecompounds of the invention can be administered in any pharmaceuticallyacceptable dosage form, such as a cream, ointment, lotion, solution,transdermal patch, etc., in an amount ranging from about 0.001 mg toabout 100 mg per dose, preferably from about 0.01 to about 10 mg perdose.

The compounds can be administered in conventional oral dosage forms suchas capsules, tablets, pills, powders, suspensions or solutions preparedwith conventional pharmaceutically acceptable excipients and additives,using conventional techniques. Parenteral preparations, i.e. sterilesolutions or suspensions are also made by conventional means. Inhalationadministration can be in the form of a nasal or oral spray. Insufflationis also contemplated. Topical dosage forms can be creams, ointments,lotions and the like. Other dosage forms which can be used aretransdermal devices.

The following examples illustrate the preparation of the compounds usedin the methods of this invention as well as pharmaceutical compositionscontaining the compounds. All temperatures are in degrees Celsius.

EXAMPLE I Preparation of1,2,3,5-tetrahydro-1,5-diphenyl-4H-pyrrolo[3,2-c][1,8]napthyridin-4-one

A. The following reagents were combined in a 5 mL vessel:2(2-chloronicotinoyl)butyrolactone (II) 0.500 g (2.22 mmol), aniline0.500 mL (4.44 mmol), and 2.0 mL MeOH (Me═CH₃). The vessel purged withargon and kept under argon during the course of the reaction. Thereaction mixture was heated to about 165° C. over a period of 2 hr, heldat about 165° C. for an additional 1/2 hr and then allowed to cool toroom temperature. The reaction mixture was triturated with 10 mL of 10%NaOH and 10 mL CH₂ Cl₂. The CH₂ Cl₂ layer was collected and evaporatedto give 0.810 g of crude product.

The crude product was purified by preparative TLC using 90:10n-BuCl:MeOH (BU═C₄ H₉) on silica. Yield after extraction and drying was0.210 g (0.605 mmol, 27.2%), mp 220°-2° C. IR, NMR, and MS spectra wereconsistent with the assigned structure. C, H, and N analyses were within0.3% of theory.

This procedure will also produce1,2,3,5-tetrahydro-1,5-bis(3-chlorophenyl)-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-one when 3-chloroaniline is substituted foraniline.

B. A mixture of1-phenyl-3-(2-hydroxyethyl)-4-hydroxy-[1,8]naphthyridin-2-one (III)0.500 g (1.73 mmol), aniline 0.500 mL (4.44 mmol), 2.00 mL EtOH, (Et═C₂H₅) and 50 ul 6N HCl was charged into a 5 mL vessel under argon andheated to about 165° C. over a period of 2 hr, then held at about 165°C. for an additional 1/2 hr and then allowed to cool to roomtemperature. The reaction mixture was triturated with 10 mL of 10% NaOHand 10 mL CH₂ Cl₂. The CH₂ Cl₂ layer was collected and evaporated togive 0.712 g of crude product.

The crude product was purified by preparative TLC using 90:10n-BuCl:MeOH (Bu═C₄ H₉) on silica. Yield after extraction and drying was0.331 g (0.976 mmol, 56.4%), mp 220°-222° C. IR, NMR, and MS wereconsistent with the assigned structure.

This procedure will also produce1,2,3,5-tetrahydro-1-(4-methoxyphenyl)-5-phenyl-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-one when 4-methoxyaniline (also known asp-anisidine) is substituted for aniline.

EXAMPLE II Preparation of1,2,3,5-tetrahydro-5-phenyl-1-(phenylmethyl)-4H-pyrrolo[3,2-c][1,8]napthyridin-4-one

A. A mixture of 0.500 g1-phenyl-3-(2-hydroxyethyl)-4-hydroxy-[1,8]naphthyridin-2-one (III)(1.73 mmol), 0.500 g benzylamine hydrochloride (3.44 mmol), and 2.00 mLEtOH was charged into a 5 mL vessel under argon and heated to about 200°C. over a period of about 2 hr, held at 200° C. for an additional 1 hand then allowed to cool to room temperature. The reaction mixture wastriturated with 5×10 mL H₂ O then with 5×10 mL of 10% NaOH. Theresulting amorphous solid was washed with H₂ O and extracted with 2×15ml refluxing toluene. Evaporation of the toluene produced crude product.Purification by preparative TLC (n-BuCL:MeOH::85:15 on silica) yielded0.123 g (0.385 mmol, 9.8%) crystalline solid. IR, NMR, and MS spectrawere consistent with the assigned structure.

This procedure will also produce1,2,3,5-tetrahydro-5-(3-chlorophenyl)-2-methyl-1-(phenylmethyl)-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-onewhen1-(3-chlorophenyl)-3-(2-hydroxypropyl)-4-hydroxy-[1,8]naphthyridin-2-oneis substituted for1-phenyl-3-(2-hydroxyethyl)-4-hydroxy-[1,8]naphthyridin-2-one.Furthermore,1,2,3,5-tetrahydro-5-(3-methoxyphenyl)-1-hydroxy-2-methyl-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-oneis produced by this procedure when4-hydroxy-1-(3-methoxyphenyl)-3-(2-hydroxypropyl)-[1,8]naphthyridin-2-oneis substituted for1-phenyl-3-(2-hydroxyethyl)-4-hydroxy-[1,8]naphthyridin-2-one andhydroxylamine hydrochloride is substituted for benzylaminehydrochloride.

B. A suspension of3,5-dihydro-5-phenylfuro[3,2-c][1,8]naphthyridin-4(2H)-one (2 g),(formula III) in benzylamine (6 mL) was heated in an inert atmosphere(N₂) at 160°-165° C. until the starting material (formula III) haddisappeared (about 24 hours), as shown by HPLC (Reverse phase C₁₈column; solvent; CH₃ CN (65); H₂ O (35); CH₃ CO₂ H (0.5). The reactiontime was about 24 hr. After cooling, the crude product was treated withether and the solid which formed was filtered off, washed with ether andtriturated with isopropanol. The yield of product was 0.75 g, identicalwith the material from Example IIA.

This procedure will also produce1,2,3,5-tetrahydro-1-(n-butyl)-5-phenyl-4H-Pyrrolo[3,2-c][1,8]naphthyridin-4-onewhen 1-phenyl-3-(2-hydroxyethyl)-4-hydroxy-[1,8]naphthyridin-2-one issubstituted for3,5-dihydro-5-phenyl-furo[3,2-c][1,8]naphthyridin-4(2H)-one andn-butylamine is substituted for benzylamine. Furthermore,1,2,3,5-tetrahydro-5-(3-chlorophenyl)-1-(2-hydroxyethyl)-2-methyl-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-onemay be produced by this procedure when1-(3-chlorophenyl)-4-hydroxy-3-(2-hydroxypropyl)-[1,8]naphthyridin-2-oneis substituted for3,5-dihydro-5-phenyl-furo[3,2-c][1,8]naphthyridin-4(2H)-one and2-hydroxyethylamine is substituted for benzylamine.

EXAMPLE III Preparation of1,2,3,5-tetrahydro-5-phenyl-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-one

Compound I (5.0 g) where R¹ =phenyl, R² =benzyl, R³ =R⁴ =H and X was CHwas mixed with 30% HBr in HOAc (25 mL). The reaction was heated to about90° C. under an N₂ atmosphere for about 1 hr. The reaction mixture wasthen poured into water (300 mL). The resulting mixture was adjusted to apH of 5.0 with NaOH solution. The product was collected by filtration.Yield was 43%, mp was >290° C. λmax in MeOH were 324 nm (ε=10500) and354 nm (ε=5500).

This procedure will also produce1,2,3,5-tetrahydro-5-(3-chlorophenyl)-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-onewhen1,2,3,5-tetrahydro-5-(3-chlorophenyl)-1-(phenylmethyl)-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-oneis substituted for the starting material compound I where R¹ is phenyl,R² is benzyl, R³ and R⁴ are H, and X is CH. Furthermore,1,2,3,5-tetrahydro-5-(4-fluorophenyl)-2-methyl-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-onemay be produced by this procedure when1,2,3,5-tetrahydro-5-(4-fluorophenyl)-2-methyl-1-(phenylmethyl)-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-oneis substituted for the starting material compound I as defined above.

EXAMPLE IV Preparation of2,3,4,5-tetrahydro-4-oxo-5-phenyl-1H-pyrrolo[3,2-c][1,8]napthyridine-1-carboxylicacid, ethyl ester

Compound I (300 mg) where R¹ =phenyl, R² =R³ =R⁴ =H and X was CH wasreacted in CH₂ Cl₂ (6 mL) with ClC(O)OEt (0.7 mL) in the presence ofexcess N,N-dimethylaminopyridine for 24 hr. The product was collected byfiltration, washed with dilute acid (0.5N HCl) then with H₂ O and dried.Yield was 83%, m.p. is 230°-233° C.

This procedure will also produce2,3,4,5-tetrahydro-4-oxo-5-(3-chlorophenyl)-1H-pyrrolo[3,2-c][1,8]naphthyridine-1-carboxylicacid, 2methylpropylester when1,2,3,5-tetrahydro-5-(3-chlorophenyl)-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-oneis substituted for the starting material compound I where R¹ is phenyl,R², R³ and R⁴ are H and X is CH.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

We claim:
 1. A compound having the structural formula XI ##STR9## or apharmaceutically acceptable salt or solvate thereof, wherein: R¹ isselected from H, alkyl having from 1 to 10 carbon atoms, aryl havingfrom 6 to 15 carbon atoms, alkenyl having from 3 to 10 carbon atoms,benzyl, substituted alkyl having from 1 to 10 carbon atoms, substitutedaryl having from 6 to 15 carbon atoms, substituted benzyl, --O(CO)--R⁸,D--NR⁵ R⁶, --D--OR⁷ or --D--(CO)--OR⁸ wherein D is alkanediyl havingfrom 1 to 8 carbon atoms or a covalent bond;R³ and R⁴ are the same ordifferent and each is independently selected from H, alkyl having from 1to 10 carbon atoms, aryl having from 6 to 15 carbon atoms or heteroarylhaving from 2 to 14 carbon atoms; R⁵ and R⁶ are the same or differentand each is independently selected from H or alkyl having from 1 to 10carbon atoms, or together represent alkanediyl having from 1 to 8 carbonatoms; R⁷ is selected from H, alkyl having from 1 to 10 carbon atoms oraryl having from 6 to 15 carbon atoms; and R⁸ is selected from alkylhaving from 1 to 10 carbon atoms, aryl having from 6 to 15 carbon atoms,benzyl or substituted benzyl.
 2. The compounds of claim 1 wherein:R¹ isselected from phenyl, benzyl, substituted phenyl or substituted benzyl;R² is selected from H, phenyl, substituted phenyl, alkyl having from 1to 10 carbon atoms, alkenyl having from 3 to 10 carbon atoms,--O(CO)--R⁸, --D--NR⁵ R⁶, --D--OH or --D--(CO)--OR⁸ wherein D isalkanediyl having from 1 to 8 carbon atoms, or a covalent bond; R³ andR⁴ are the same or different and each is independently selected from Hor alkyl having from 1 to 10 carbon atoms; R⁵ and R⁶ are the same ordifferent and each is independently selected from H or alkyl having from1 to 10 carbon atoms, or together represent alkanediyl having from 1 to8 carbon atoms; and R⁸ is selected from alkyl having from 1 to 10 carbonatoms or aryl having from 6 to 15 carbon atoms.
 3. The compounds ofclaim 2 wherein said substituent on said substituted phenyl orsubstituted benzyl is selected from halogen, nitro, alkyl having from 1to 10 carbon atoms or alkoxy having from 1 to 10 carbon atoms.
 4. Thecompounds of claim 2 wherein R¹ is phenyl; andR² is selected fromphenyl, benzyl, H or (CO)OR⁸.
 5. The compounds of claim 4 wherein R² isH or (CO)OR⁸.
 6. The compounds of claim 5 wherein R² is H.
 7. Thecompounds of claim 5 wherein R² is (CO)OR⁸.
 8. The compounds of claim 4wherein R² is benzyl.
 9. The compounds of claim 4 wherein R² is phenyl.10. The compounds of claim 4 wherein R³ and R⁴ are H.
 11. Apharmaceutical composition which comprises a compound having structuralformula XI as defined in claim 1, in combination with a pharmaceuticallyacceptable carrier.
 12. A method for treating inflammation in a mammalcomprising administering to said mammal an anti-inflammatory effectiveamount of a compound as claimed in claim
 1. 13. The method of claim 12wherein said anti-inflammatory effective amount is 0.5 to 50 mg/kg/day,administered orally.
 14. The method of claim 12 wherein saidanti-inflammatory effective amount is 0.1 to 10 mg/kg/day, administeredintravenously.
 15. A method for treating hyperproliferative skin diseasein a mammal comprising administering to said mammal anantihyperproliferative effective amount of a compound as claimed inclaim
 1. 16. The method of claim 15 wherein said antihyperproliferativeeffective amount is 0.01 to 100 mg/kg, administered orally orparenterally.
 17. The method of claim 15 wherein saidantihyperproliferative effective amount is 0.001 to 100 mg/kgadministered topically.